Synthetic derivatives and analogs of anthraquinone are a valuable group of cytostatics. Among developed compounds of this type, 1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]-9,10-anthracenodione, known under the International Non-proprietary Name (INN) mitoxantrone, is in clinical use as antitumor drug. However, appearance of phenotypic, multidrug cross resistance of tumor cells (MultiDrug Resistance—MDR), causes the loss of therapeutic efficacy of antitumor drugs, even chemically and functionally unrelated ones, including mitoxantrone.
The phenomenon of MDR depends on overexpression of genes coding for membrane proteins exporting from cell xenobiotics such as cytostatics and thus preventing from retaining therapeutic concentration of drug in cell. Three groups of such glycoprotein type proteins have been discovered, among them MDR-1 (so called P-gp), BCRP protein and MRP proteins group. These proteins differ by their substrate spectrum towards cytostatics interacting with them. However, this spectrum is very broad and includes many structural groups of antitumor chemotherapeutics.
The phenomenon of multidrug resistance prompts the necessity of searching for new cytostatics which would be active against the resistant cells, including also anthraquinone group drugs. Different strategies for the design of these compounds were developed
(E. Borowski et al., Acta Biochim. Polon. 52, 609, 2005). The most promising strategy concerns the design of compounds which are poor substrates of proteins responsible for MDR phenomenon. This strategy gives the best chance to improve drug selectivity and reduce the adverse side effects. Considering however very broad substrate spectrum of MDR proteins the effects of these studies are not satisfactory up to now. It was found that antymetabolites as 5-fluorouracil, are not recognizable by xenobiotics exporting MDR pomps because of their structural similarity to natural metabolites uracil. Only a few other antitumor drugs have been shown to be rather poor substrates for MDR pomps. One important exception is taxol, which however is the MDR-1 pomp substrate, but is not the substrate of MRP pomp and thus exhibits activity towards tumor cells with overexpression of this pomp.
Among important group of cytostatics the analogs and derivatives of antraquinone, none of them has been as yet introduced to clinical practice, for the treatment of drug resistant tumors.
Until now, among synthesized mitoxantrone analogs and derivatives, some activity in relation to resistant cells show compounds, possessing an additional heterocycling ring fused to the anthraquinone moiety. They are compounds with pyrazole ring fused to the chromophore system (H. Showalter et al., Anti-Cancer Drug Design 1, 73, 1986), pyridine ring (P. Krapcho et al., J. Med. Chem., 37, 823, 1994), pyridazone ring (C. Gandolfii, J. Med. Chem. 38, 526, 1995), pyrimidine ring (B. Stefańska et al., J. Med. Chem. 36, 38, 1993) or pyridazone ring i. e. anthrapyridazone derivatives (B. Stefańska et al., Bioorg. Med. Chem., 11, 561, 2003).
Among antrapyridazones described in Bioorg. Med. Chem., 11, 561, 2003, revealed are derivatives symmetrically di- substituted at positions 2- and 6- with dimethylaminoethyl or piperidineethyl moieties. Also one asymmetrically substituted compound with dimethylaminoethyl group at position 2- and piperidineethyl group at position 6- has been described. Some of these derivatives exhibited some in vitro cytotoxic activity against selected tumor cells, such as murine leukemia L1210 cells and human K562, but low activity against multidrug resistant subline of human leukemia K562/DX. There are no data on the activity of these compounds towards the cells of solid tumors.
In Dzieduszycka's et al. publication, Polish J. Chem., 81, 535, 2007, the synthesis of pentacyclic anthrapyridazone analogs with additional ring forming imidazole or phthalazine system has been described, however, no data on the biological properties of obtaining compounds are shown.
The new compounds according to the present invention, being assymmetrically substituted anthrapyridazone derivatives, exhibit significant cytotoxic activity towards multidrug resistant tumor cells. For the first time it was found that among anthrapyridazone analogs and derivatives this activity results from the fact that they are poor MDR exporting proteins substrates. As mentioned above this is the advantageous mechanism of counteraction to the activity of pomp exporting cytostatic from cells. This way of activity of anthrapyridazone derivatives, especially asymmetrically substituted ones till now has not been known.